American Journal of Epidemiology - Advance Access

Use of Nonsteroidal Antiinflammatory Drugs and Risk of Endometrial Cancer

Bodelon, C., Doherty, J. A., Chen, C., Rossing, M. A., Weiss, N. S. — Fri, 06 Nov 2009 01:08:44 PST

Results of 3 previous studies suggest that use of aspirin is related to a reduced risk of endometrial cancer, at least in obese women (body mass index, ≥30 kg/m²). Using data obtained in a population-based, case-control study in western Washington State, the authors examined this question. Between 2003 and 2005, 410 women diagnosed with invasive endometrial cancer and 356 controls were interviewed regarding the use of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). A history of use of NSAIDs was not associated with the risk of endometrial cancer (odds ratio = 1.04, 95% confidence interval: 0.76, 1.42). The lack of association was also present specifically for use of aspirin (odds ratio = 1.06, 95% confidence interval: 0.73, 1.53). NSAID use was unrelated to risk of endometrial cancer in both obese and nonobese women. Results from this study suggest that the use of aspirin or other NSAIDs has little or no influence on the risk of endometrial cancer.

Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions

Fri, 06 Nov 2009 01:08:44 PST

The individual effect of functional single nucleotide polymorphisms within the catalase and myeloperoxidase genes (CAT and MPO) has been studied in relation to asthma; however, their interrelationship with ambient air pollution exposures has yet to be determined. The authors investigated the interrelationships between variants in CAT and MPO, ambient air pollutants, and acute respiratory illness. Health information, air pollution, and incident respiratory-related school absences were ascertained in January–June 1996 for 1,136 Hispanic and non-Hispanic white US elementary schoolchildren as part of the prospective Children's Health Study. Functional and tagging single nucleotide polymorphisms for the CAT and MPO loci were genotyped. The authors found epistasis between functional polymorphisms in the CAT/MPO loci, which differed by levels of oxidant-stress-producing air pollutants. Risk of respiratory-related school absences was elevated for children with the CAT (G/G) and MPO (G/A or A/A) genes (relative risk = 1.35, 95% confidence interval: 1.03, 1.77; P-interaction = 0.005). The epistatic effect of CAT and MPO variants was most evident in communities exhibiting high ambient ozone levels (P-interaction = 0.03). The association of respiratory-illness absences with functional variants in CAT and MPO that differ by air pollution levels illustrates the need to consider genetic epistasis in assessing gene-environment interactions.

Timing and Trajectories of Fetal Growth Related to Cognitive Development in Childhood

von Ehrenstein, O. S., Mikolajczyk, R. T., Zhang, J. — Wed, 04 Nov 2009 00:53:43 PST

The authors investigated timing and trajectories of fetal growth in relation to childhood development in the National Institute of Child Health and Human Development–Scandinavian Study of Successive Small-for-Gestational Age Births (1986–1988) (n = 1,059). Fetal size was assessed by ultrasound at 17, 25, and 33 gestational weeks and at birth. Bayley Scales of Infant Development and the Wechsler Preschool and Primary Scale of Intelligence-Revised tests were conducted at ages 1 and 5 years, respectively, producing mental and psychomotor development indexes and verbal and performance intelligence quotients. Relative fetal size was calculated as a standard deviation score at each data point; growth trajectories were explored with longitudinal mixture models. Fetal size at 17, 25, and 33 weeks was positively associated with mental development index; larger size at 33 weeks and at birth was associated with higher verbal intelligence quotient scores (2.61, 95% confidence interval: 1.06, 4.15 and 1.90, 95% confidence interval: 0.67, 3.13 increase per 1 standard deviation score, respectively); findings were similar for performance intelligence quotient. Seven trajectories were identified; scores were lower for "small" and "medium-to-small" trajectories than for "medium" and "big" (representing normal size) trajectories: mental development index (P < 0.01), performance intelligence quotient (P < 0.001), and verbal intelligence quotient (P < 0.001). Overall, larger fetal size in the second and third trimesters was positively associated with childhood development. Fetal growth trajectories may matter beyond birth.

Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study

Wed, 04 Nov 2009 00:53:41 PST

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

Harold A. Kahn (1920-2009): A Remembrance of a Life Devoted to Public Health

Sempos, C. T., Goldbourt, U. — Tue, 03 Nov 2009 01:40:18 PST

Population-based, Case-Control-Family Design to Investigate Genetic and Environmental Influences on Melanoma Risk: Australian Melanoma Family Study

Tue, 03 Nov 2009 01:40:17 PST

Discovering and understanding genetic risk factors for melanoma and their interactions with phenotype, sun exposure, and other risk factors could lead to new strategies for melanoma control. This paper describes the Australian Melanoma Family Study, which uses a multicenter, population-based, case-control-family design. From 2001 to 2005, the authors recruited 1,164 probands including 629 cases with histopathologically confirmed, first-primary cutaneous melanoma diagnosed before age 40 years, 240 population-based controls frequency matched for age, and 295 spouse/friend controls. Information on lifetime sun exposure, phenotype, and residence history was collected for probands and nearly 4,000 living relatives. More than 3,000 subjects donated a blood sample. Proxy-reported information was collected for childhood sun exposure and deceased relatives. Important features of this study include the population-based, family-based design; a focus on early onset disease; probands from 3 major cities differing substantially in solar ultraviolet exposure and melanoma incidence; a population at high risk because of high ultraviolet exposure and susceptible pigmentation phenotypes; population-based, spouse/friend, and sibling controls; systematic recruitment of relatives of case and control probands; self and parent reports of childhood sun exposure; and objective clinical skin examinations. The authors discuss methodological and analytical issues related to the study design and conduct, as well as the potentially novel insights the study can deliver.

THE FIRST AUTHOR REPLIES

Salomon, J. A. — Sun, 01 Nov 2009 23:23:45 PST

RE: "ARE AMERICANS FEELING LESS HEALTHY? THE PUZZLE OF TRENDS IN SELF-RATED HEALTH"

Avendano, M., Huijts, T., Subramanian, S. V. — Sun, 01 Nov 2009 23:23:44 PST

Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis

Sun, 01 Nov 2009 23:23:44 PST

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5–12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-µm increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.

Use of Fertility Drugs and Risk of Uterine Cancer: Results From a Large Danish Population-based Cohort Study

Jensen, A., Sharif, H., Kjaer, S. K. — Sun, 01 Nov 2009 23:23:42 PST

Some epidemiologic studies have indicated that uterine cancer risk may be increased after use of fertility drugs. To further assess this association, the authors used data from a large cohort of 54,362 women diagnosed with infertility who were referred to Danish fertility clinics between 1965 and 1998. In a case-cohort study, rate ratios and 95% confidence intervals were used to assess the effects of 4 groups of fertility drugs on overall risk of uterine cancer after adjustment for potentially confounding factors. Through mid-2006, 83 uterine cancers were identified. Ever use of any fertility drug was not associated with uterine cancer risk (rate ratio (RR) = 1.10, 95% confidence interval (CI): 0.69, 1.76). However, ever use of gonadotropins (follicle-stimulating hormone and human menopausal gonadotropin) increased uterine cancer risk (RR = 2.21, 95% CI: 1.08, 4.50); the risk was primarily observed after 10 years of follow-up. Furthermore, uterine cancer risk increased with number of cycles of use for clomiphene (for ≥6 cycles, RR = 1.96, 95% CI: 1.03, 3.72) and human chorionic gonadotropin (for ≥6 cycles, RR = 2.18, 95% CI: 1.16, 4.08) but not for other gonadotropins. Use of gonadotropin-releasing hormone analogs was not associated with risk. Gonadotropins, and possibly clomiphene and human chorionic gonadotropin, may increase the risk of uterine cancer, with higher doses and longer follow-up leading to greater risk.

Effect of Supplemental Folic Acid in Pregnancy on Childhood Asthma: A Prospective Birth Cohort Study

Whitrow, M. J., Moore, V. M., Rumbold, A. R., Davies, M. J. — Fri, 30 Oct 2009 07:03:41 PDT

This study aimed to investigate the effect of the timing, dose, and source of folate during pregnancy on childhood asthma by using data from an Australian prospective birth cohort study (n = 557) from 1998 to 2005. At 3.5 years and 5.5 years, 490 and 423 mothers and children participated in the study, respectively. Maternal folate intake from diet and supplements was assessed by food frequency questionnaire in early (<16 weeks) and late (30–34 weeks) pregnancy. The primary outcome was physician-diagnosed asthma, obtained by maternal-completed questionnaire. Asthma was reported in 11.6% of children at 3.5 years (n = 57) and in 11.8% of children at 5.5 years (n = 50). Folic acid taken in supplement form in late pregnancy was associated with an increased risk of childhood asthma at 3.5 years (relative risk (RR) = 1.26, 95% confidence interval (CI): 1.08, 1.43) and with persistent asthma (RR = 1.32, 95% CI: 1.03, 1.69). The effect sizes did not change with adjustment for potential confounders. The association was similar at 5.5 years but did not reach statistical significance (RR = 1.17, 95% CI: 0.96, 1.42) in univariable models. These findings on childhood asthma support previous observations that supplementation with folate in pregnancy leads to an allergic asthma phenotype in mice via epigenetic mechanisms and is associated with poorer respiratory outcomes in young children.

Mammographic Screening and Risk Factors for Breast Cancer

Cook, N. R., Rosner, B. A., Hankinson, S. E., Colditz, G. A. — Thu, 29 Oct 2009 11:37:50 PDT

Screening mammography can distort estimated effects in breast cancer risk models due to associations with other risk factors. Mammography information was available in the Nurses’ Health Study from 1988, and 1,815 incident breast cancers were accrued through 2000 among 55,625 women with risk factor data. Logistic models were fit for screening mammography, and inverse probability weighting was used to adjust parameters in an established breast cancer risk model. Approximately 80% of women in each 2-year follow-up period had screening mammograms, which were positively associated with history of benign breast disease, family history of breast cancer, hormone therapy, alcohol use, physical activity, multivitamins, and calcium supplements, and negatively associated with postmenopause, current smoking, and body mass index. Markers of medical attention, including hypertension, high cholesterol, and osteoarthritis, were positively associated, while cardiovascular disease was negative. Inverse probability weighting led to small changes in effects of benign breast disease, family history, and hormone therapy. An apparent reduced risk associated with current smoking in unadjusted models was eliminated after weighting. Thus, several risk factors for breast cancer and cancer diagnosis are associated with mammographic screening. Adjustment for screening had some impact on breast cancer prediction in this cohort, especially for hormone therapy and smoking.

International Ethical Guidelines for Epidemiological Studies: By the Council for International Organizations of Medical Sciences (CIOMS)

Rose, S. — Wed, 28 Oct 2009 11:16:06 PDT

Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis

Ragland, M., Hutter, C., Zabetian, C., Edwards, K. — Wed, 28 Oct 2009 11:16:03 PDT

The ubiquitin carboxyl-terminal esterase L1 gene, UCHL1, located on chromosome 4p14, has been studied as a potential candidate gene for Parkinson's disease risk. The authors conducted a Human Genome Epidemiology review and meta-analysis of published case-control studies of the UCHL1 S18Y variant and Parkinson's disease in Asian and Caucasian samples. The meta-analysis of studies in populations of Asian ancestry showed a statistically significant association between the Y allele and reduced risk of Parkinson's disease under a recessive model (odds ratio (OR) for YY vs. SY + SS = 0.79, 95% confidence interval (CI): 0.67, 0.94; P = 0.006). For a dominant model, the association was not significant in Asian populations (OR for YY + SY vs. SS = 0.88, 95% CI: 0.68, 1.14; P = 0.33). For populations of European ancestry, the meta-analysis showed a significant association between the Y allele and decreased risk of Parkinson's disease under a dominant model (OR = 0.89, 95% CI: 0.81, 0.98; P = 0.02) but not under a recessive model (OR = 0.92, 95% CI: 0.66, 1.30; P = 0.65). Using the Venice criteria, developed by the Human Genome Epidemiology Network Working Group on the assessment of cumulative evidence, the authors concluded that moderate evidence exists for an association between the S18Y variant and Parkinson's disease.

Maternal Effects for Preterm Birth: A Genetic Epidemiologic Study of 630,000 Families

Fri, 23 Oct 2009 03:57:31 PDT

This study was undertaken to disentangle the maternal genetic from the fetal genetic effects for preterm birth and to study the possibility of these effects being explained by known risk factors. By cross-linking of the population-based Swedish Multigeneration and Medical Birth registers, 989,027 births between 1992 and 2004 were identified. Alternating logistic regression was applied to model the familial clustering with pairwise odds ratios (PORs), and covariates were included to evaluate if the familial aggregation was explained by exposure to shared risk factors. Generalized linear mixed models were used to estimate the contribution of genetic and environmental effects. Sisters of women who had a preterm delivery had themselves an increased odds of having a preterm delivery (POR = 1.8, 95% confidence interval: 1.5, 2.1), while there was no corresponding increase in odds in families joined by brothers (POR = 1.1, 95% confidence interval: 0.9, 1.4). Twenty-five percent of the variation in preterm birth was explained by maternal genetic factors, whereas fetal genetic factors only marginally influenced the variation in liability. The increased odds ratio between offspring of sisters was independent of maternal risk factors for preterm birth, suggesting that the relative importance of maternal effects is not explained by these well-known risk factors.

Svensson et al. Respond to "Maternal Genes and Environment in Preterm Birth"

Fri, 23 Oct 2009 03:57:30 PDT

Invited Commentary: Maternal Effects in Preterm Birth--Effects of Maternal Genotype, Mitochondrial DNA, Imprinting, or Environment?

Little, J. — Fri, 23 Oct 2009 03:57:29 PDT

Preterm birth is an important public health problem. A wide range of risk factors has been investigated, of which the strongest established is a woman's previous history of preterm birth. In this issue of the Journal, Boyd et al. (Am J Epidemiol. 2009;170(00):0000–0000) and Svensson et al. (Am J Epidemiol. 2009;170(00):0000–0000), using data on singleton livebirths from national birth registers linked with multigeneration databases, found evidence that maternal genetic factors impact on the risk for preterm birth, whereas paternal and probably fetal genetic factors do not. Possible caveats include missing information, the range of maternal risk factors included in the analyses, possible misclassification of these risk factors, and possible vertical transmission of microbial flora or behaviors from mother to daughter. Weinberg and Shi (Am J Epidemiol. 2009;170(00):0000–0000) build on the evidence regarding potential mechanisms underlying the heritability of preterm birth from these 2 and other studies, to evaluate the comparative ability of different study designs to distinguish among these potential mechanisms. These studies have different strengths, and a portfolio of studies of different designs and with more detailed phenotyping than previously done will be needed to probe further the etiology of preterm birth and thereby provide tools for its control.

The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies

Weinberg, C. R., Shi, M. — Fri, 23 Oct 2009 03:57:29 PDT

Women delivering preterm are at greatly increased risk of another preterm birth in subsequent pregnancies, reflecting effects of the environment, genetics, or both. Recent literature tells an increasingly coherent story about genetic susceptibility. Women who change partners after delivering preterm retain their elevated risk, whereas fathers who change partners do not. Women who themselves were preterm are at increased risk, an association not seen in fathers. Women with a half-sister who delivered preterm are at increased risk only if the shared parent was the mother. Concordance for preterm delivery is elevated in monozygotic compared with dizygotic twin mothers but not in monozygotic twin fathers. Several mechanisms could be operating: mitochondrial genes, maternal genes, or fetal genes expressing only the maternally derived copy. The authors compare 3 study designs for their ability to detect variants and to distinguish among mechanisms underlying heritability of this common outcome. The case-parent triad design offers robustness against self-selection and genetic population stratification, providing for estimation of genetic effects that are fetal, maternal, or that depend on the parent of origin. A case-base approach compares case-mothers with randomly sampled baby-mother pairs and permits estimation of the same relative risk parameters. Both designs offer important advantages over the commonly applied case-mother/control-mother design.

Maternal Contributions to Preterm Delivery

Boyd, H. A., Poulsen, G., Wohlfahrt, J., Murray, J. C., Feenstra, B., Melbye, M. — Fri, 23 Oct 2009 03:57:28 PDT

Preterm delivery (PTD) is a complex trait with a significant familial component. However, no specific inheritance patterns have been established. The authors examined the contribution of PTDs in both the woman's family and her partner's family to her risk of PTD. The authors linked birth information from Danish national registers with pedigree information from the Danish Family Relations Database for 1,107,124 live singleton deliveries occurring from 1978 to 2004. Risk ratios were estimated comparing women with and without various PTD histories. Women with previous PTDs were at greatly increased risk of recurrent PTD (risk ratio = 5.6, 95% confidence interval: 5.5, 5.8); however, their PTD risk was unaffected by a partner's history of preterm children with other women. PTDs to a woman's mother, full sisters, or maternal half-sisters also increased her PTD risk (risk ratio = 1.6, 95% confidence interval: 1.5, 1.6), whereas PTDs in her paternal half-sisters, the female partners of her male relatives, or members of her partner's family did not affect her PTD risk. Inheritance patterns were similar for all gestational ages from very early through late PTD. The substantial portion of PTD risk explained by effects passed through the female line suggests a role for either imprinting or mitochondrial inheritance.

Estimation of the Contribution of Non-Assisted Reproductive Technology Ovulation Stimulation Fertility Treatments to US Singleton and Multiple Births

Schieve, L. A., Devine, O., Boyle, C. A., Petrini, J. R., Warner, L. — Fri, 23 Oct 2009 03:57:27 PDT

Infertility treatments that include ovulation stimulation, both assisted reproductive technologies (ARTs) and non-ART ovulation stimulation, are associated with increased risks of multiple birth and concomitant sequelae and adverse outcomes, even among singletons. While a US surveillance system for ART-induced births is ongoing, no population-based tracking system exists for births resulting from non-ART treatments. The authors developed a multistage model to estimate the uncertain proportion of US infants born in 2005 who were conceived by using non-ART ovulation treatments. Using published surveillance data, they estimated proportions of US multiple births conceived naturally and by ART and assumed that the remainder were conceived with non-ART treatments. They used Bayesian meta-analyses to summarize published clinical studies on the multiple-gestation risk associated with non-ART ovulation treatments, applied a fetal survival factor, and used this multiple-birth risk estimate and their own estimate of the proportion of US multiple births attributable to non-ART ovulation stimulation to estimate the total (and, through subtraction, singleton) proportion of infants conceived with such treatments. On the basis of the model, the authors estimate that 4.6% of US infants born in 2005 (95% uncertainty range: 2.8%–7.1%) resulted from non-ART ovulation treatments. Notably, this figure is 4 times greater than the ART contribution.

Newly Reported Respiratory Symptoms and Conditions Among Military Personnel Deployed to Iraq and Afghanistan: A Prospective Population-based Study

Thu, 22 Oct 2009 05:04:52 PDT

Concerns about respiratory conditions have surfaced among persons deployed to Iraq and Afghanistan. Data on 46,077 Millennium Cohort Study participants who completed baseline (July 2001–June 2003) and follow-up (June 2004–February 2006) questionnaires were used to investigate 1) respiratory symptoms (persistent or recurring cough or shortness of breath), 2) chronic bronchitis or emphysema, and 3) asthma. Deployers had a higher rate of newly reported respiratory symptoms than nondeployers (14% vs. 10%), while similar rates of chronic bronchitis or emphysema (1% vs. 1%) and asthma (1% vs. 1%) were observed. Deployment was associated with respiratory symptoms in both Army (adjusted odds ratio = 1.73, 95% confidence interval: 1.57, 1.91) and Marine Corps (adjusted odds ratio = 1.49, 95% confidence interval: 1.06, 2.08) personnel, independently of smoking status. Deployment length was linearly associated with increased symptom reporting in Army personnel (P < 0.0001). Among deployers, elevated odds of symptoms were associated with land-based deployment as compared with sea-based deployment. Although respiratory symptoms were associated with deployment, inconsistency in risk with cumulative exposure time suggests that specific exposures rather than deployment in general are determinants of postdeployment respiratory illness. Significant associations seen with land-based deployment also imply that exposures related to ground combat may be important.

"Proportion Explained": A Causal Interpretation for Standard Measures of Indirect Effect?

Hafeman, D. M. — Thu, 22 Oct 2009 05:04:51 PDT

The assessment of indirect effects is an important tool for epidemiologists interested in exploring the mechanisms of exposure-disease relations. A standard way of expressing an indirect effect is in terms of the "proportion explained"; this is the proportion of the total effect that is explained by a particular mediator (or set of mediators). There are several ways to calculate the proportion explained, based on both additive and multiplicative models. However, these standard methods (particularly those based on multiplicative models) have been criticized for lacking a causal interpretation. To address this issue, the author uses a framework of potential outcomes to define the indirect effects of interest (natural effects) and assess the correspondence between the natural effects and standard measures. The author finds that standard additive measures represent an unbiased weighted average of the effects of interest; standard multiplicative measures, on the other hand, yield a biased weighted average of these effects. If the investigator is primarily interested in whether or not an indirect effect exists, standard measures for mediation will often yield the correct answer. In contrast, if valid quantification of the indirect effect is desired, counterfactual-based methods should be used.

A Dictionary of Epidemiology, Fifth Edition: Edited by Miquel Porta

Samet, J. M., Wipfli, H., Platz, E. A., Bhavsar, N. — Mon, 12 Oct 2009 00:34:33 PDT